Breast cancer is the second most common type of cancer and related mortality in women in most countries causing 519,000 deaths worldwide in 2004 alone. Two main types of breast cancer are estrogen receptor (ER) positive cancers, wherein ER is over-expressed, and HER2 positive cancers, wherein human epidermal growth factor 2 (HER2) is overexpressed compared to normal breast tissue cells (M. Nadji, C. Gomez-Fernandez, P. Ganjei-Azar, A. R. Morales, Immunohistochemistry of estrogen and progesterone receptors reconsidered: experience with 5,993 breast cancers. Am J Clin Pathol 123 (2005) 21-27). The majority of breast cancers is ER-positive and requires estrogen for growth and progression. The binding of estrogen to ER changes its conformation and leads to the release of the receptor from heat shock proteins (HSPs), the release promoting dimer formation of the ER monomers. The dimerized ERs recruit their co-activators to stimulate target gene expression. Encoded proteins can promote cell division, resulting in fast proliferation and metastasis (K. A. Green, J. S. Carroll, Oestrogen-receptor-mediated transcription and the influence of co-factors and chromatin state. Nat Rev Cancer 7 (2007) 713-722) (FIG. 1).
Overexpression of the HER2 receptor in breast cancer cells is associated with increased disease recurrence and worse prognosis. HER2 is a cell membrane surface-bound receptor tyrosine kinase and is normally involved in the signal transduction pathways leading to cell growth and differentiation. It is encoded by HER2/neu, a known proto-oncogene. HER2 is thought to be an orphan receptor, with none of the EGF family of ligands able to activate it. However, other ErbB receptors dimerise on ligand binding, and HER2 is the preferential dimerization partner of other members of the ErbB family.
Currently, the most commonly used drug for treating ER-positive breast cancer is tamoxifen, which can bind to ER and inhibit its binding to the receptor's co-activators, therefore preventing target gene transcription. Although tamoxifen is very effective in treating ER-positive breast cancer, it has limitations. First, tamoxifen is not effective in about 30% of breast cancer patients. Second, tamoxifen resistance has been observed in 80% of patients after 15 months of treatment (A. Howell, D. DeFriend, J. Robertson, R. Blarney, P. Walton, Response to a specific antioestrogen (ICI-182780) in tamoxifen-resistant breast cancer. Lancet 345 (1995) 29-30). Third, clinical evidence suggests that cells overexpressing HER2 are more likely to become tamoxifen resistant. Although therapies that target HER2 have been developed, including trastuzumab, a monoclonal antibody, and lapatinib, a tyrosine kinase inhibitor, the available therapies are very expensive and resistance to these drugs has been reported as well.
Thus, there is still need for alternative treatment regimens for breast cancer that overcome the known problems.